TNF-α-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IκB-NFκB and JAK-STAT3 pathways.

Interleukin (IL)-6 is an important mediator of neurovascular dysfunction, neurodegeneration and/or neuroinflammation. We previously reported that brain pericytes released higher levels of IL-6 than did glial cells (astrocytes and microglia) in response to tumor necrosis factor (TNF)-α. Moreover, pericytes stimulated with TNF-α enhanced activation of BV-2 microglia. In this study, we investigated the mechanisms of TNF-α mediated induction of IL-6 release from brain pericytes and astrocytes and whether pericyte-derived IL-6 would facilitate activation of BV-2 microglia. Using rat brain pericyte and astrocyte primary cultures and pharmacological inhibitors, we found that, TNF-α induced the highest levels of IL-6 release from pericytes by activating the inhibitor kappa B (IκB)-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT)3 pathways. STAT3 contributed to TNF-α induced nuclear translocation of phospho-NFκB in pericytes. TNF-α-induced IL-6 release in astrocytes was mediated by NFκB but not by STAT3. The presence of pericytes amplified TNF-α-induced iNOS mRNA expression in BV-2 microglia. This effect was blocked by a neutralizing antibody for IL-6. These findings indicated that crosstalk between the IκB-NFκB and JAK-STAT3 pathways is a pericyte specific mechanism, not occurring in astrocytes, for TNF-α-induced IL-6 release. IL-6 derived from pericytes enhanced microglial activation. Our findings increase understanding of the role of pericyte-microglia crosstalk in the brain under neuroinflammatory conditions and suggest a potentially attractive therapeutic target for brain inflammation.

Serum vitamin D in patients with mild cognitive impairment and Alzheimer's disease.

Objectives: To determine the relevance of Mini-Mental State Examination (MMSE), serum 25-hydroxyvitamin D (25(OH)D3), and 1,25(OH)2D3 concentrations to mild cognitive impairment (MCI) and various stages of Alzheimer's disease (AD). Materials and Methods: The study included 230 participants (>74 years) allocated to three main groups: 1-healthy subjects (HS, n = 61), 2-patients with MCI (n = 61), and 3- patients with Alzheimer's disease (AD) subdivided into three stages: mild (n = 41), moderate (n = 35), and severe AD (n = 32). The cognitive status was evaluated using MMSE. Serum 25 (OH)D3 (ng/ml) and 1,25(OH)2D3 concentrations (pg/ml) were determined by competitive radioimmunoassay. Results: MMSE scores and 25(OH)D3 were decreased in MCI and all stages of the AD in both genders. MMSE variability was due to gender in HS (11%) and to 25(OH)D3 in MCI (15%) and AD (26%). ROC analysis revealed an outstanding property of MMSE in diagnosis of MCI (AUC, 0.906; CI 95%, 0.847-0.965; sensitivity 82%; specificity, 98%) and AD (AUC, 0.997; CI 95%, 0.992-1; sensitivity, 100%; specificity, 98%). 25(OH)D3 exhibited good property in MCI (AUC, 0.765; CI 95%, 0.681-0.849; sensitivity, 90%; specificity, 54%) and an excellent property in diagnosis of AD (AUC, 0.843; CI 95%, 0.782-0.904; sensitivity, 97%; specificity, 79%). Logistic analyses revealed that, in MCI, MMSE could predict (or classify correctly) with 97.6% accuracy (Wald, 15.22, ß, -0.162; SE, 0.554; OR = 0.115:0.039-0.341; p = .0001), whereas 25(OH)D3 with 80% accuracy (Wald, 41,013; ß, -0.213; SE, 0.033; OR = 0.808: 0.757-863; p = .0001). 25(OH)D3 was the only significant predictor for the severe AD and contributed to MMSE variability. Age and gender were significant predictors only in the moderate AD. In patients with MCI, 25(OH)D3 and 1,25(OH)2D3 were correlated men, but in case of the AD, they were correlated in women. Conclusions: MMSE and serum 25(OH)D3 concentrations could be useful biomarkers for prediction and diagnosis of MCI and various stages of the AD. The results support the utility of vitamin D supplementation in AD therapy regimen.

Effect of varenicline on behavioral deficits in a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine lesion of substantia nigra.

Nicotinic acetylcholine receptors (nAChRs) are implicated in the pathogenesis of Parkinson's disease (PD). Varenicline tartrate is a partial agonist at α4ß2 and full agonist at α7 neuronal nAChR subunits. A unilateral lesion of the substantia nigra (SN) has been used as a reliable model of PD. This study aimed to investigate the effect of varenicline on locomotor and nonlocomotor behavioral deficits induced by a unilateral lesion of the SN induced by 6-hydroxydopamine (6-OHDA) (8 µg/4 µl). Varenicline (1 mg/kg) was administered to the lesioned rats daily for 2 weeks, which commenced 3 weeks after 6-OHDA administration. The results showed that varenicline improved motor deficits induced by 6-OHDA. It improved locomotor and nonlocomotor activities such as forelimb use, rotarod performance, and forelimb asymmetry. Varenicline did not change rearing or vibrissae-elicited forelimb placing but did increase apomorphine-induced rotation. In conclusion, the present results suggest that drugs with specific partial/full agonistic activity on nAChR subunits could be of value in the treatment of neurodegenerative disorders such as PD.

Effect of Angiotensin-(1-7) on Aortic Response, TNF-α, IL-1ß and Receptor for Advanced Glycation Endproduct in Rat's Adjuvant-Induced Arthritis.

Altered vascular reactivity due to endothelial dysfunction, consequent to vascular damage, is observed in rheumatoid arthritis. We investigated the effect of angiotensin (Ang)-(1-7) on vasculature changes in arthritis induced by complete Freund's adjuvant in male Wistar rats. Arthritis decreased soluble receptor for advanced glycation end products (sRAGE) whereas elevated aortic RAGE expression, increased interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), systolic blood pressure and the contractility induced by phenylephrine and KCl. Moreover, arthritis decreased the relaxing effect of acetylcholine. Neither arthritis nor Ang-(1-7) altered sodium nitroprusside relaxation. Ang-(1-7) reversed the effect of arthritis on TNF-α, sRAGE and RAGE expression without any effect on the IL-1ß. Ang-(1-7) decreased phenylephrine and KCl contractility, especially in the endothelial-denuded aorta, whereas increased acetylcholine relaxation in the endothelial-intact aorta. Ang-(1-7) could find its place in the treatment protocol of arthritis and vascular diseases.

Effects of ß-sheet breaker peptides on altered responses of thoracic aorta in rats' Alzheimer's disease model induced by intraamygdaloid Aß40.

AIMS: Alzheimer's disease (AD) is characterized by vascular dysfunction, in addition to memory impairment. Previously we found that ß-sheet breaker peptides (ßSBPs) improved memory impairment induced by amyloid ß-peptide Aß40. In this study we investigated ßSBP effects on vascular responses in a rat model of AD. MAIN METHODS: AD model was induced by bilateral injection of aged Aß40 (3 nmol) into the amygdala. ßSBPs 15-22, 16-23 and 17-24 (30 nmol) were injected into the amygdala 8 days after Aß40. The Aß40 deposits were examined immunohistochemically in cerebral vessels and thoracic aorta. The effects on high-K(+) contractility, phenylephrine (PE) contractility, acetylcholine (ACh) relaxation and sodium nitroprusside (SNP) relaxation were investigated in isolated thoracic aorta. Nitric oxide (NO) level in serum was investigated 14 days after Aß40. KEY FINDINGS: Aß40 was localized and it induced vascular damage in minute and small perforating cerebral vascular endothelium, and tunica intima (endothelial) and media (smooth muscle cells) of the thoracic aorta. In intact aorta, ACh-relaxation was decreased by Aß40, an effect reduced by ßSBPs 15-22 and 16-23. In denuded aorta, Aß40 decreased PE-contractility. ßSBP15-22 increased ACh-relaxation, whereas ßSBP17-24 increased K(+)-contraction. Aß40 decreased NO, an effect inhibited by the ßSBP15-22. SIGNIFICANCE: These results provide evidence that Aß40-perverted endothelium-dependent relaxation and decreased serum NO in AD rats were improved differentially by the ßSBP15-22. These results show the ability of Aß40 to alter vascular responses. ßSBPs appear to be promising candidate for prevention of these consequences and therapy of AD.

Modulation of the negative inotropic effect of haloperidol by drugs with positive inotropic effects in isolated rabbit heart.

Haloperidol is a typical antipsychotic drug with inhibitory effects on dopamine and calcium homeostasis. In this study, the effect of haloperidol on the inotropism of rabbits' isolated heart was investigated by measuring the isovolumetric left ventricular pressure using a balloon in a modified Langendorff perfusion apparatus. Haloperidol at 0.01-0.3 micromol/l induced a negative inotropic effect (E(max) = 77.95 +/- 0.19; EC(50) = 0.043 +/- 0.002 micromol/l). The effect of haloperidol was decreased by Ca(2+) (E(max) = 42.93 +/- 3.22; EC(50) = 0.37 +/- 0.07 micromol/l; pD'(2) = 7.01 +/- 0.16), Bay K 8644 (E(max) = 30.75 +/- 1.33; EC(50) = 10.43 +/- 1.5 micromol/l, pD'(2) = 7.13 +/- 0.12), and digoxin (E(max ) = 42.03 +/- 3.72, EC(50) = 0.32 +/- 0.05 micromol/l, pD'(2) = 6.81 +/- 0.14). The effect of haloperidol was also reduced by norepinephrine (E(max) = 37.16 +/- 1.84; EC(50) = 1.73 +/- 0.24 micromol/l, pD'(2) = 6.97 +/- 0.08) and dopamine (E(max) = 35.68 +/- 2.78; EC(50) = 0.69 +/- 0.01 micromol/l, pD'(2 )7.48 +/- 0.15). However, the effect of haloperidol was nonsignificantly reduced by dobutamine (E(max) = 58.89 +/- 5.18; EC(50) = 0.15 +/- 0.06 micromol/l, pD'(2) = 5.88 +/- 0.47). These results show that the drugs that increase the influx of Ca(2+) into the cardiomyocyte decrease the negative inotropic effect of haloperidol, suggesting that the effect of haloperidol could be mediated via mechanisms involving actions on Ca(2+) entry into the cardiomyocyte. Haloperidol should be used carefully when prescribed for patients with cardiovascular disorders.